This invention relates to the analysis of blood coagulation time as it is influenced by differing concentrations of additive reagents, and more particularly to apparatus and methods for performing the analysis of blood coagulation time.
It is well-known in the practice of clinical medicine to inhibit the coagulation of blood by administering various anticoagulant medications. One such medication, heparin, is particularly important because its effects as well as its neutralization by the agent, protamine, are essentially instantaneous. Widely used in early treatment of thromboembolic disease, herapin's most noteworthy applications are in the fields of extracorporeal circulation such as cardiovascular surgery and hemodialysis. An excellent article giving a survey of the herapin therapy field is entitled "Inappropriate Response to Herapin" by H. B. Soloway, Diagnostic Medicine, Sept./Oct. 1979, pages 31-33.
Protocols for heparin therapy administration and control are usually based upon a prescribed prolongation of coagulation time as determined by some clot timing technique. Protocols which prescribe a heparin dose based upon patient's sex, weight and height fail to account for variations in patient response to herapin. Such problems and a proposed solution are discussed by Bull, et al., "Heparin therapy during extracorporeal circulation: I. Problems inherent in existing heparin protocols; II. The use of a dose-responsive curve to individualize heparin and protamine doseage," 69 J. Throacic Card. Surg. 674-689 (1975). Application of the method of Bull, et al to the system described in U.S. Pat. No. 3,695,842 issued to Michael D. Mintz, the inventor herein, is explained by Kersting and Rush, "A Simple Individualized Method for Dose-Responsive Heparin and Protamine Administration," 11 J. Extra-Corp. Tech. 56-60 (1979). Briefly described, the dose-responsive technique is an in vivo method in which coagulation time tests are performed on blood samples taken before and after a patient has been given one or two bolus heparin infusions. The resulting data, plotted as heparin vs coagulation time, are used to determine current heparin level, maintenance dose requirement and protamine neutralization dose implied by subsequent coagulation time tests.
U.S. Pat. No. 4,000,972 entitled MEASURING SYSTEM FOR THE PHARMACOLOGICAL MANIPULATION OF THE COAGULATION MECHANISM IN BLOOD AND FOR THE ELAPSED COAGULATION TIME issued to Braun, et al. on Jan. 4, 1977, describes a system and method of protamine titration of heparin-medicated blood in which a single blood sample is divided into a plurality of test chambers. Thereafter, differing amounts of protamine are injected into each chamber and mixed with the blood aliquots. The test is terminated upon first observation of clotting in one of the chambers. The protamine concentration in the chamber thus identified is designated by the system as the neutralizing protamine concentration. A calculator section of the system subsequently interprets this data, in conjunction with certain operator-input patient and protocol data to yield the patient's specific protamine dose requirement. By equating the neutralizing protamine concentration to heparin concentration and comparing this implied level of heparinization with the operator-input, heparin maintenance level, the calculator section computes a heparin make-up dose for the patient. This prior art system has the advantages of performing analyses on a single sample of blood. Test results are essentially independent of the temperature conditions to which the various test chambers are simultaneously subject, and they are readily understood by the operator.
The system of Braun, et al. has several disadvantages. First, the coagulation time reported by the analyzer is representative of the neutralized sample after addition of protamine, not of the blood as it may be flowing in patient or extracorporeal circuit. Second, the basis for selecting the first observed clotted chamber as that containing the exact neutralizing protamine concentration is, as stated by the inventors, "--too much protamine results in anticoagulated blood--." While this statement is generally accepted as factual for large concentrations of protamine, Perkins, et al., "Neutralization of heparin invivo with protamine; A simple method of estimating the required dose", 48 J. Lab. & Clin. Med. 223-226 (1956) has shown that protamine concentrations of as much as three times the neutralizing concentration in heparinized blood may exhibit essentially identical coagulation times. In-as-much as all clot detectors are characterized by some degree of statistical uncertanty, it will be seen that the first clotted blood specimen in this prior art system may randomly contain protamine concentrations between one and three times the desired levels.
Another disadvantage of this prior art system is that it is limited to use in heparin therapy protocols that seek to maintain or control heparin concentration. It has been shown by several researchers (see for example, Berg, et al., "Monitoring heparin and protamine therapy during cardiopulmonary bypass by activated clotting time" 11 J. Ext.-Corp. Tech. 229-235 (1979), however, that the heparin dose required to prolong coagulation to a specific activated clotting time value of say 480 seconds may vary from 100 to 700 units per kilogram of body weight. Hence, control of blood heparin concentration alone may be inadequate to prevent clotting during critical extracorporeal procedures.